De novo ATP1A3 variants cause polymicrogyria

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Polymicrogyria is a common yet poorly understood congenital brain malformation.
• The genetic underpinnings of many cortical development disorders remain largely unknown.

Purpose of the Study:

• To investigate the genetic etiology of polymicrogyria.
• To identify novel genetic factors contributing to severe polymicrogyria with epilepsy and developmental delay.

Main Methods:

• Whole-exome sequencing was performed on 124 patients diagnosed with polymicrogyria.
• Functional studies in mouse models were used to assess the impact of identified variants on neuronal development.

Main Results:

• De novo variants in the ATP1A3 gene were identified in eight patients with a distinct polymicrogyria phenotype.
• These ATP1A3 variants differed in location and functional impact from those previously associated with known neurological disorders like AHC, RDP, and CAPOS.
• Overexpression of a severe patient-derived ATP1A3 variant impaired radial neuronal migration in developing mouse cerebral cortex.

Conclusions:

• ATP1A3 gene abnormalities represent a previously unrecognized cause of a severe polymicrogyria subtype.
• This discovery broadens the spectrum of ATP1A3-related neurological disorders and provides new insights into cortical malformation pathogenesis.